Discovery of Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries

使用 DNA 编码化学文库发现碳青霉烯酶抑制剂

• 批准号: 10538574
• 负责人: Timothy Palzkill
• 金额: $ 60.43万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-18 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10538574
• 关键词: Active Sites; Affinity; Ampicillin; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Area; Bacteria; Bacterial Drug Resistance; Bacterial Infections; Bar Codes; Carbapenems; Cephalosporins; Characteristics; Chemicals; Clavulanic Acids; Clinic; Clinical; Collection; Complex; DNA; Drug resistance; Enterobacteriaceae; Enzyme Inhibitor Drugs; Enzymes; Escherichia coli; Future; Goals; Gram-Negative Bacteria; Hospitals; Hydrolysis; Infection; Lactams; Libraries; Medicine; Methods; Monobactams; Multi-Drug Resistance; Names; Penicillins; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasmids; Predisposition; Production; Public Health; Rod; Roentgen Rays; Serine; Source; Structure; Structure-Activity Relationship; Technology; Work; antimicrobial drug; bacterial resistance; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; carbapenem resistance; carbapenemase; clinically relevant; college; drug development; drug discovery; drug-like compound; experimental study; improved; inhibitor; innovation; insight; novel; pathogen; resistance mechanism; scaffold; small molecule; small molecule inhibitor; small molecule libraries; virtual

Project Summary/Abstract Because of their favorable characteristics, β-lactams make up approximately 60% of antibiotic usage worldwide. Bacterial resistance to β-lactam drugs, however, has been steadily increasing, posing a significant threat to antibiotic therapy. The most common mechanism of resistance is β-lactamase-catalyzed hydrolysis, which renders the antibiotics ineffective. An area of particular concern is multi-drug resistant infections caused by Gram-negative rods; leaving few options for treatment. Carbapenems are a class of β-lactam antibiotics that historically have been less susceptible to the action of β-lactamases and have seen increased usage. A rising number of bacterial infections acquired in hospital settings, however, are caused by carbapenem resistant Enterobactericiae (CRE) pathogens. Enterobacteriaceae frequently become resistant to carbapenem antibiotics by acquiring plasmid-encoded β-lactamases named carbapenemases. The three most frequently encountered carbapenemases in clinics worldwide are KPC-2, NDM-1, and OXA-48. The objective of this application is to utilize DNA-encoded chemical library technology to discover small molecule inhibitors of these enzymes. This approach involves the creation of libraries of drug-like molecules covalently attached to a unique DNA barcode that enables identification of binders for a target in a large pool of compounds. DNA-encoded chemical libraries have been constructed at the Center for Drug Discovery at Baylor College of Medicine that encode over 2 billion compounds, allowing a screen of wide chemical space for novel, non-β-lactam inhibitors of these important drug-resistance enzymes. In preliminary studies, we demonstrated the feasibility of the approach by using a DNA-encoded chemical library to identify CDD-97, which inhibits OXA-48 with a Ki of 600 nM. The X-ray structure of OXA-48 in complex with CDD-97 revealed it makes key interactions with active site residues and medicinal chemistry studies have defined structure-activity relationships for the molecule. DNA-encoded chemical library screens will be extended for the OXA-48, NDM-1 and KPC-2 β-lactamases and identified inhibitors will be characterized with respect to potency of inhibition, X-ray structure, spectrum of inhibition, and bioactivity versus bacteria. In addition, medicinal chemistry methods will be used to optimize potency and accumulation of inhibitors in bacteria. The proposed experiments have the potential to yield new, non-β-lactam, inhibitors and provide insights into chemical scaffolds that are favorable for interaction with β-lactamases.

项目摘要/摘要 由于其有利的特征，β-内酰胺大约占抗生素使用的60％ 全世界。然而，对β-内酰胺药物的细菌耐药性一直在稳步增加，构成A 对抗生素疗法的重大威胁。阻力的最常见机制是 β-内酰胺酶催化的水解，使抗生素无效。一个特定的区域 concern is multi-drug resistant infections caused by Gram-negative rods;几乎没有选择 治疗。碳青霉烯是一类β-内酰胺抗生素，历史上较少 容易受到β-内乳酶的作用，并看到使用增加了。数量上升 然而 肠杆菌病原体。肠杆菌科经常对碳青霉烯具有抵抗力 通过获取质粒编码的β-内酰胺酶，抗生素称为碳二酰酶。三个 全球诊所经常遇到的碳青霉酶是KPC-2，NDM-1和OXA-48。 该应用的目的是利用DNA编码的化学图书馆技术发现小 这些酶的分子抑制剂。这种方法涉及创建类似毒品的图书馆 共同附着在独特的DNA条形码上的分子，该条形码能够鉴定A 靶向大量化合物。 DNA编码的化学文库已在 贝勒医学院的药物发现中心，编码超过20亿种化合物， 允许为这些重要的新型非β-内酰胺抑制剂提供广泛的化学空间 抗药性酶。在初步研究中，我们证明了该方法的可行性 使用DNA编码的化学文库鉴定CDD-97，该CDD-97抑制OXA-48的Ki为600 nm。 与CDD-97复合物中OXA-48的X射线结构表明，它与 主动部位保留和医学化学研究已确定了结构活性关系 分子。 DNA编码的化学库筛网将用于OXA-48，NDM-1和 KPC-2 β-lactamases and identified inhibitors will be characterized with respect to potency of 另外，X射线结构，抑制范围以及生物活性与细菌。 药物化学方法将用于优化抑制剂的效力和积累 细菌。提出的实验有可能产生新的非β-内酰胺，抑制剂和 提供有利于与β-内酰胺酶相互作用的化学支架的见解。

项目成果

Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48.

• DOI: 10.1021/acsinfecdis.1c00501
• 发表时间: 2021-12-10
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Taylor, Doris Mia;Anglin, Justin;Hu, Liya;Wang, Lingfei;Sankaran, Banumathi;Wang, Jin;Matzuk, Martin M.;Prasad, B. V. Venkataram;Palzkill, Timothy
• 通讯作者: Palzkill, Timothy